Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln)

CA658658781

456652 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: a6aa2394-0263-45c0-85a1-98fbd1d26b0c

HGVS expressions

NM_000527.5:c.2231_2232delinsAG
NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln)
NC_000019.10:g.11123264_11123265delinsAG
CM000681.2:g.11123264_11123265delinsAG
NC_000019.9:g.11233940_11233941delinsAG
CM000681.1:g.11233940_11233941delinsAG
NC_000019.8:g.11094940_11094941delinsAG
NG_009060.1:g.38884_38885delinsAG
ENST00000558518.6:c.2231_2232delinsAG
ENST00000252444.9:n.2485_2486delinsAG
ENST00000455727.6:c.1727_1728delinsAG
ENST00000535915.5:c.2108_2109delinsAG
ENST00000545707.5:c.1697_1698delinsAG
ENST00000557933.5:c.2231_2232delinsAG
ENST00000558013.5:c.2231_2232delinsAG
ENST00000558518.5:c.2231_2232delinsAG
NM_000527.4:c.2231_2232delinsAG
NM_001195798.1:c.2231_2232delinsAG
NM_001195799.1:c.2108_2109delinsAG
NM_001195800.1:c.1727_1728delinsAG
NM_001195803.1:c.1697_1698delinsAG
NM_001195798.2:c.2231_2232delinsAG
NM_001195799.2:c.2108_2109delinsAG
NM_001195800.2:c.1727_1728delinsAG
NM_001195803.2:c.1697_1698delinsAG

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 25
PS1 PS3 PS2 PS4 BP2 BP3 BP1 BP5 BP7 BA1 PP4 PP1 PP3 PP2 PM5 PM1 PM3 PM4 PM6 PM2 PVS1 BS2 BS3 BS4 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.2231_2232delinsAG (p.Arg744Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence code BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - No REVEL, splicing evaluation needed. Functional studies are not available A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site and creates de novo AG site. MES scores: de novo variant = -3.1; canonical acceptor = 8.76. Ratio de novo variant/canonical acceptor =-3.1/8.76 = -0.35 -> it is below 0.8.
Met criteria codes
BP4
No REVEL, splicing evaluation needed. Functional studies are not available A) variant not on limits. B) variant is exonic and at least 50bp downstream from the canonical acceptor site and creates de novo AG site. MES scores: de novo variant = -3.1; canonical acceptor = 8.76. Ratio de novo variant/canonical acceptor =-3.1/8.76 = -0.35 -> it is below 0.8.
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-05-27
Published on: 2022-12-23
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